Mitf regulates osteoclastogenesis by modulating NFATc1 activity.
Mitf regulates osteoclastogenesis by modulating NFATc1 activity.
复制标题
DOI：
10.1016/j.yexcr.2014.08.018
复制
发表时间：
2014-10-15
影响因子：
3.7
通讯作者：
Lin, Yi-Ling
中科院分区：
文献类型：
--
作者：
Lu, Ssu-Yi;Li, Mengtao;Lin, Yi-Ling
转录因子Mitf和NFATc 1共享许多对破骨细胞生成至关重要的下游靶点。由于RANKL信号诱导/激活NFATc 1和Mitf亚型-E（Mitf-E）（破骨细胞中的一种组织限制性Mitf亚型），因此这两种因子共同促进破骨细胞生成似乎是合理的。虽然Mitf在NFATc 1的上游发挥作用，但本研究表明，Mitf的表达对NFATc 1的影响很小，NFATc 1对Mitf-E的诱导至关重要。在Mitfmi/mi小鼠中，Mitf基因的半显性突变导致破骨细胞生成在早期阶段被阻止。然而，当受RANKL刺激时，Mitfmi/mi前破骨细胞响应于NFATc 1的显著诱导，尽管细胞不能分化为功能性破骨细胞。在不存在RANKL刺激的情况下，需要非常高水平的NFATc 1来驱动破骨细胞发育。我们的数据表明，Mitf在RANKL通路中的NFATc 1下游发挥作用，并且在放大NFATc 1依赖的破骨细胞生成信号中起重要作用，这有助于破骨细胞生成过程中两个因子之间的显著协同作用。我们认为Mitf-E在破骨细胞生成过程中作为NFATc 1激活下游事件的组织特异性调节剂发挥作用。
Transcription factors Mitf and NFATc1 share many downstream targets that are critical for osteoclastogenesis. Since RANKL signals induce/activate both NFATc1 and Mitf isoform-E (Mitf-E), a tissue-restricted Mitf isoform in osteoclasts, it is plausible that the two factors work together to promote osteoclastogenesis. Although Mitf was shown to function upstream of NFATc1 previously, this study showed that expression of Mitf had little effects on NFATc1 and NFATc1 was critical for the induction of Mitf-E. In Mitfmi/mi mice, the semi-dominant mutation in Mitf gene leads to arrest of osteoclastogenesis in the early stages. However, when stimulated by RANKL, the Mitfmi/mi preosteoclasts responded with a significant induction of NFATc1, despite that the cells cannot differentiate into functional osteoclasts. In the absence of RANKL stimulation, very high levels of NFATc1 are required to drive osteoclast development. Our data indicate that Mitf functions downstream of NFATc1 in the RANKL pathway, and it plays an important role in amplifying NFATc1-dependent osteoclastogenic signals, which contributes to the significant synergy between the two factors during osteoclastogenesis. We propose that Mitf-E functions as a tissue-specific modulator for events downstream of NFATc1 activation during osteoclastogenesis.
登录
查看更多内容
影响因子：
4.8
作者：
Mansky, KC;Sankar, U;Ostrowski, MC
通讯作者：
Ostrowski, MC
影响因子：
15.3
作者：
Asagiri, M;Sato, K;Takayanagi, H
通讯作者：
Takayanagi, H
影响因子：
4.8
作者：
Choi, Jiwon;Choi, So Yoen;Lee, Na Kyung
通讯作者：
Lee, Na Kyung
影响因子：
15.9
作者：
Aliprantis, Antonios O.;Ueki, Yasuyoshi;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
影响因子：
4.8
作者：
Hirotani, H;Tuohy, NA;Clipstone, NA
通讯作者：
Clipstone, NA